Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide Peptides.

The synthesis of rare macrocyclic alkynediyl sulfides by a Cu-catalyzed Csp -S cross-coupling is presented. The catalytic protocol (Cu(MeCN)4 PF6 /dtbbpy) promotes macrocyclization of peptides, dipeptides and tripeptides at ambient temperature (14 examples, 23→73 % yields) via thiols and bromoalkynes, and is chemoselective with regards to terminal alkynes. Importantly, the underexplored alkynediyl sulfide functionality incorporates a rigidifying structural element and opens new opportunities for diversification of macrocyclic frameworks through S oxidation, halide addition and azide-alkyne cycloaddition chemistries to integrate sulfones, halides or valuable fluorophores (7 examples, 37→92 % yields).

Biocatalytic synthesis of planar chiral macrocycles.

Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features.

Photocatalyic Appel reaction enabled by copper-based complexes in continuous flow.

A copper-based photocatalyst, Cu(tmp)(BINAP)BF4, was found to be active in a photoredox Appel-type conversion of alcohols to bromides. The catalyst was identified from a screening of 50 complexes and promoted the transformation of primary and secondary alcohols to their corresponding bromides and carboxylic acids to their anhydrides. The protocol was also amendable and optimized under continuous flow conditions.

Heteroleptic Copper(I)-Based Complexes for Photocatalysis: Combinatorial Assembly, Discovery, and Optimization.

A library of 50 copper-based complexes derived from bisphosphines and diamines was prepared and evaluated in three mechanistically distinct photocatalytic reactions. In all cases, a copper-based catalyst was identified to afford high yields, where new heteroleptic complexes derived from the bisphosphine BINAP displayed high efficiency across all reaction types. Importantly, the evaluation of the library of copper complexes revealed that even when photophysical data is available, it is not always possible to predict which catalyst structure will be efficient or inefficient in a given process, emphasizing the advantages for catalyst structures with high modularity and structural variability.

Photochemical Dual-Catalytic Synthesis of Alkynyl Sulfides.

A photochemical dual-catalytic cross-coupling to form alkynyl sulfides via C(sp)-S bond formation is described. The cross-coupling of thiols and bromoalkynes is promoted by a soluble organic carbazole-based photocatalyst using continuous flow techniques. Synthesis of alkynyl sulfides bearing a wide range of electronically and sterically diverse aromatic alkynes and thiols can be achieved in good to excellent yields (50-96 %). The simple continuous flow setup also allows for short reaction times (30 min) and high reproducibility on gram scale. In addition, we report the first application of photoredox/nickel dual catalysis towards macrocyclization, as well as the first example of the incorporation of an alkynyl sulfide functional group into a macrocyclic scaffold.